rs761921681

chr10-102504195-C-Achr10-102504195-C-Gchr10-102504195-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM5 PP2 BP4_Moderate BS1_Supporting BS2

The NM_016169.4(SUFU):c.43C>A(p.Pro15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,569,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15L) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.15

Genes affected

SUFU (HGNC:16466): (SUFU negative regulator of hedgehog signaling) The Hedgehog signaling pathway plays an important role in early human development. The pathway is a signaling cascade that plays a role in pattern formation and cellular proliferation during development. This gene encodes a negative regulator of the hedgehog signaling pathway. Defects in this gene are a cause of medulloblastoma. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-102504196-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3569.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, SUFU
• BP4: Computational evidence support a benign effect (MetaRNN=0.10585758).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000501 (71/1417684) while in subpopulation NFE AF= 0.0000632 (69/1092008). AF 95% confidence interval is 0.0000508. There are 0 homozygotes in gnomad4_exome. There are 24 alleles in male gnomad4_exome subpopulation. Median coverage is 46. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUFU	NM_016169.4	c.43C>A	p.Pro15Thr	missense_variant	1/12	ENST00000369902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUFU	ENST00000369902.8	c.43C>A	p.Pro15Thr	missense_variant	1/12	1	NM_016169.4	P1
SUFU	ENST00000423559.2	c.43C>A	p.Pro15Thr	missense_variant	1/10	1
SUFU	ENST00000369899.6	c.43C>A	p.Pro15Thr	missense_variant	1/11	1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000170 AC: 3 AN: 176570 Hom.: 0 AF XY: 0.0000308 AC XY: 3 AN XY: 97320

Gnomad AFR exome AF: 0.000116

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000501 AC: 71 AN: 1417684 Hom.: 0 Cov.: 46 AF XY: 0.0000342 AC XY: 24 AN XY: 701814

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000632

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74328

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000304 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000174 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 32 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 13, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 15 of the SUFU protein (p.Pro15Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SUFU-related conditions. ClinVar contains an entry for this variant (Variation ID: 453965). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The p.P15T variant (also known as c.43C>A), located in coding exon 1 of the SUFU gene, results from a C to A substitution at nucleotide position 43. The proline at codon 15 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	0.91	N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.35	N;N;N
REVEL	Benign	0.069
Sift	Benign	0.039	D;D;D
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.28
MutPred		0.27		Gain of phosphorylation at P15 (P = 0.0017);Gain of phosphorylation at P15 (P = 0.0017);Gain of phosphorylation at P15 (P = 0.0017);
MVP		0.27
MPC		1.3
ClinPred		0.13	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs761921681; hg19: chr10-104263952; COSMIC: COSV105926748; COSMIC: COSV105926748;